Skeletal muscle disuse is an important contributing factor to physical disability. Disuse is more frequent in the elderly and they are more susceptible to its debilitating effects because of their diminished physiological reserve. Despite these facts, the mechanisms whereby disuse promotes skeletal muscle contractile dysfunction in this population remain largely undetermined. Therefore, we propose to systematically test for modifications of single muscle fiber structure and function that underlie contractile dysfunction. Elderly individuals characterized by chronic muscle disuse will be compared to carefully-matched controls with normal activity levels. Thereafter, elderly with chronic disuse will undergo an exercise intervention to remediate muscle disuse. We hypothesize that muscle disuse impairs contractile function, in part, through alterations in myosin kinetics, myofilament protein content and the mechanical properties of the myofilament lattice and that exercise rehabilitation will counteract these deficits. Aim 1 will examine the effect of disuse on mechanical, kinetic and structural properties and molecular composition of single muscle fibers in cases and controls. Aim 2 will investigate how increasing muscle use in elderly with chronic disuse via exercise training affects muscle fiber mechanical, kinetic and structural properties and molecular composition. Innovations in our laboratories have enabled assessment of muscle function at the level of the myosin-actin cross-bridge in humans for the first time. In combination with other mechanical, biochemical and anatomical measurements, these translational studies will provide the first comprehensive evaluation of the cellular and molecular mechanisms through which muscle disuse alters skeletal muscle structure and contractile function in elderly humans. This knowledge can assist in the development and refinement of preventative and corrective therapies for disability by tailoring these approaches to address specific molecular defects. PUBLIC HEALTH RELEVANCE: Skeletal muscle disuse is an important contributing factor to disability in the elderly. Despite the fact that elderly are more likely to experience disuse and lack the physiological reserve to buffer its detrimental effects, the cellular and molecular mechanisms that underlie disuse-related muscle contractile dysfunction remain largely unstudied. Knowledge gained from the proposed studies will assist in the development and refinement of preventative and corrective clinical therapies for disability by tailoring these approaches to address specific cellular and molecular defects.